Is ERAP1 p.Arg127Pro (c.380G>C) pathogenic?

ERAP1 p.Arg127Pro (c.380G>C) is classified Benign in ERAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). AlphaMissense: likely benign (0.0658); Common (popmax 72.1%, nfe) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ERAP1 p.Arg127Pro (c.380G>C)?

AlphaMissense predicts likely benign (score 0.0658) — an in-silico prediction, not a clinical call.

ERAP1 p.Arg127Pro

Q: How common is ERAP1 p.Arg127Pro (c.380G>C) in the general population?

ERAP1 p.Arg127Pro (c.380G>C) is common (popmax 72.1%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.380G>C · rs26653 · VCV2688544

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0658 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 72.1%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0658	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -4.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -1.5
Regional constraint	o/e 0.86	unconstrained · MANE · 10 kb · p 0.003 · regional, not allelic
Overall
CADD	1.757	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 72.1% European (non-Finnish) · 850,142/1,179,586 alleles

Filtering AF 71.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 71.9%

Overall 68.4% 1,102,794/1,613,416 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	72.1%	1
Finnishnot grpmax-eligible	71.5%	1
Remaining individualsnot grpmax-eligible	66%	2
Middle Eastern	60.9%	2
Amishnot grpmax-eligible	59%	2
Ashkenazi Jewishnot grpmax-eligible	58.4%	2
Admixed American	56.8%	2
South Asian	54.1%	2
African / African-American	52%	2
East Asian	48.7%	2

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ERAP1
Protein: p.Arg127Pro
Coding: c.380G>C
MANE Select: NM_001040458
dbSNP: rs26653
Type: single nucleotide variant
Location: chr5:96803547 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.78 · 27 PDB
Residue 127: a UniProt-annotated variant site (in); a turn

Full ERAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERAP1 p.Ala356= Benign ★★ same type
ERAP1 p.Gly514Arg Benign/Likely benign ★★ same type
ERAP1 p.Ile915Thr Likely benign ★★ ⚠ same type
ERAP1 p.Ser18= Benign/Likely benign ★★ same type
ERAP1 p.Tyr57= Benign/Likely benign ★★ same type
ERAP1 p.Tyr789= Benign ★★ same type
ERAP2 p.Leu411Arg Benign/Likely benign ★★ ⚠ same type
CAST p.Leu618Phe Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/erap1-p-arg127pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown